S100A9 is a functional effector of infarct wall thinning after myocardial infarction

Abstract

Neutrophils infiltrate into the left ventricle (LV) early after myocardial infarction (MI) and launch a pro-inflammatory response. Along with neutrophil infiltration, LV wall thinning due to cardiomyocyte necrosis also peaks at day 1 in the mouse model of MI. To understand the correlation, we examined a previously published dataset that included day 0 (n=10) and MI day 1 (n=10) neutrophil proteome and echocardiography assessments. Out of 123 proteins, 4 proteins positively correlated with the infarct wall thinning index (1/wall thickness): histone 1.2 (r=0.62, p=0.004), S100A9 (r=0.60, p=0.005), histone 3.1 (r=0.55, p=0.01), and fibrinogen (r=0.47, p=0.04). As S100A9 was the highest ranked secreted protein, we hypothesized that S100A9 is a functional effector of infarct wall thinning. We exogenously administered S100A8/A9 at the time of MI to mice (C57BL/6J, male, 3-6 months of age, n=7M (D1), and n=5M (D3)) and compared to saline vehicle control treated mice (n=6M (D1) and n=6M (D3)) at MI days 1 and 3. At MI day 3, the S100A8/A9 group showed a 22% increase in the wall thinning index compared to saline (p=0.02), along with higher dilation and lower ejection fraction. The decline in cardiac physiology occurred subsequent to increased neutrophil and macrophage infiltration at MI day 1 and increased macrophage infiltration at D3. Our results reveal that S100A9 is a functional effector of infarct wall thinning.

Macrophages secrete murinoglobulin-1 and galectin-3 to regulate neutrophil degranulation after myocardial infarction

“…37,38 Increased neutrophil activity can induce wall thinning after MI and lead to LV aneurysms and death due to LV rupture. 35,39 LV wall thinning after MI peaks at D1, which occurs due to the loss of cardiomyocytes resulting from ischemia. Neutrophils remove the necrotic debris and lay ground for ECM deposition to form the scar by releasing ECM degrading enzymes from its granules.…”

“…through macrophages. 35 While rupture is not as common in humans with the advent of reperfusion, excessive wall thinning can lead to LV aneurysms and dilation. 68,69 Hence, treatments that limit excessive wall thinning could potentially prove useful in preventing poor outcomes.…”

“…For the time course of MI samples, the tissue was obtained from the mouse heart attack research tool (mHART) tissue bank. 35,71 All MI samples selected had undergone cardiac ligation surgery and cardiac physiology measurements by echocardiography as per the published guidelines. 72–74 Infarct size was calculated using adobe photoshop as the percentage of the area infarcted over the total area from the images of MI hearts stained by 2,3,5-triphenyl tetrazolium chloride (TTC).…”

“…[31][32][33] Since, Lgals3 interacts with soluble fibrinogen, a neutrophil protein increased in MI D1 that correlates with infarct wall thinning, we hypothesized Lgals3 could be another macrophage secreted protein that affected neutrophil physiology. 34,35 The design for this experiment is detailed in Fig. 5B.…”

Faster skin wound healing predicts survival after myocardial infarction

“…High-throughput proteomics can give mechanistic insight into the process of wound healing as well as identify biomarkers for improved diagnostics ( 20 ). A limitation of current proteomic techniques is that albumin, a highly abundant plasma protein, limits the identification of less abundant plasma proteins ( 21 , 22 ).…”